ABSTRACT: Lipid metabolism disruption as a consequence of mitochondrial dysfunction in Friedreich?s ataxia Friedreich?s Ataxia (FA) is an untreatable autosomal recessive disorder with a typical onset in children and young adults, 10 7.4 years. Currently there is no approved therapy for FA. FA is characterized by progressive mobility loss, impairment of speech, and eventual loss of vision and hearing. Individuals with FA exhibit neurodegeneration and hypertrophic cardiomyopathy. FA pathology is attributed entirely to a guanine- adenine-adenine (GAA) repeat expansion in intron 1 of the gene for frataxin, a mitochondrial protein involved in the iron-sulfur cluster biogenesis. In platelets from FA patients, decreased conversion of glucose to the central metabolic intermediate acetyl-CoA has been observed and is consistent with diminished pyruvate oxidation in FA fibroblasts. Murine models of FA have shown lipid accumulation in different organs and increased sphingolipid levels and PDK1 activity in the hearts of FA patients. Reduced frataxin also reduces the level of Nrf2. The resultant chronic elevation of oxidative stress in FA patients and animal models may be a contributing factor in the activation of cytokines responsible for COX-2 overexpression. The COX-2 lipid products derived from arachidonic acid are important bioactive lipids and their increase has been noted in FA mouse models and likely contribute to FA pathophysiology. We hypothesize that dysregulation in mitochondrial metabolic pathways will lead to dysregulated metabolomic and lipidomic profiles and could provide a rich set of biomarkers of the disease that could be complementary to the RNA data currently available and that fibroblasts provide a surrogate tissue to study the pathology of the disease and to discover new biomarkers of FA. Since fibroblast cells are not directly involved in disease pathogenesis, we will validate our fibroblast findings with whole blood from FA patients. This will be accomplished by the following specific aims. In Aim1: We will Quantify the differences between the central carbon metabolites in the fibroblasts from FA patients and healthy controls; In Aim 2: We will quantify the differences between the lipids from the sphingolipid/PDK1/Mef2 and COX-2 pathways in the fibroblasts from FA patients and healthy controls; In Aim 3: We will validate the fibroblast findings by measuring whole blood metabolomics and lipidomics in FA patients and healthy controls.